Horizant (gabapentin enacarbil XR) / Azurity Pharma, Astellas, GSK - LARVOL DELTA

The evolving treatment landscape of restless legs syndrome. (PubMed, Ther Adv Neurol Disord) - "Contemporary guidelines, culminating in the 2025 American Academy of Sleep Medicine recommendations, formalize this shift by endorsing α2δ ligands (gabapentin, pregabalin, and gabapentin enacarbil) and intravenous iron as first-line treatments, while discouraging routine use of dopamine agonists due to long-term risks. Future directions will likely depend on mechanism-based drug development, improved biomarkers, and precision medicine approaches. Overall, the evolution of RLS treatment reflects a broader transition toward sustainable, individualized care in chronic neurological disorders."

Journal • Review • CNS Disorders • Hematological Disorders • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Placebo and nocebo responses in gabapentin enacarbil and pregabalin trials for restless legs syndrome: time-course model-based network meta-analysis and meta-analysis of proportions. (PubMed, Sleep Breath) - No abstract available

Journal • Retrospective data • Review • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Benefit-risk comparison of gabapentin enacarbil versus pregabalin for restless legs syndrome: A dose-response model-based network meta-analysis. (PubMed, Sleep Breath) - No abstract available

Benefit-risk assessment • Journal • Retrospective data • Review • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Restless legs syndrome treatment - gabapentinoids or dopamine agonists? (PubMed, Neurol Neurochir Pol) - "The first-line treatment options with a "strong recommendation" are now gabapentinoids (gabapentin, gabapentin enacarbil, pregabalin) along with intravenous ferric carboxymaltose...In older patients with co-morbidities in whom gabapentinoids are not well tolerated it results in relatively high rates of withdrawal. In this point of view paper, we present our personal views (supported by clinical data) on the need for both groups of medications in clinical practice because none of them is free of potential side effects and may still be useful."

Journal • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Risks of tramadol and gabapentin use for pain. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Pain

Restless Legs Syndrome: A Review. (PubMed, JAMA) - "If possible, medications associated with RLS, including serotonergic antidepressants, dopamine antagonists, and centrally acting H1 antihistamines (eg, diphenhydramine), should be discontinued. Gabapentinoids (eg, gabapentin, gabapentin enacarbil, pregabalin) are first-line pharmacologic therapy...Dopamine agonists (eg, ropinirole, pramipexole, rotigotine) are no longer recommended as first-line medications due to the risk of augmentation, an iatrogenic worsening of RLS symptoms, which has an annual incidence of 7% to 10% with these medications. Patients who do not improve with first-line treatment or have augmented RLS often benefit from low-dose opioids (eg, methadone 5-10 mg daily)...Initial management includes cessation of exacerbating medications, as well as iron supplementation for patients with low-normal iron indices. If medication therapy is indicated, gabapentinoids are first-line treatment."

Clinical • Journal • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Congestive Heart Failure • Coronary Artery Disease • Depression • Diabetic Neuropathy • Heart Failure • Hematological Disorders • Movement Disorders • Multiple Sclerosis • Nephrology • Pain • Parkinson's Disease • Psychiatry • Renal Disease • Restless Legs Syndrome • Sleep Disorder • Suicidal Ideation

Restless Eyes at Night: A Novel Variant of Restless Legs Syndrome. (PubMed, Eur J Case Rep Intern Med) - "Restless legs syndrome (RLS) variants can affect body parts beyond the lower limbs, including the eyes.Symptoms are typically nocturnal and relieved by voluntary movement or sensory stimulation.Gabapentin enacarbil may be effective in treating these atypical RLS presentations."

Journal • Dry Eye Disease • Movement Disorders • Ophthalmology • Pain • Restless Legs Syndrome • Sleep Disorder

Partial endorsement of "Treatment of restless legs syndrome and periodic limb movement disorder: an AmericanAcademy ofSleep Medicine clinical practice guideline" by the World Sleep Society. (PubMed, Sleep Med) - "The AASM guidelines received broad international support but require region-specific adaptation for optimal implementation. The WSS endorses the guideline's structure and scientific foundation while recommending flexible dissemination strategies and greater clarity in therapeutic algorithms. These findings support the development of globally relevant, context-sensitive guidance in sleep medicine."

Clinical guideline • Journal • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Subclinical Augmentation in Relation to Previous Dopaminergic Treatment in Patients with Restless Legs Syndrome: A Post Hoc Analysis of Two Randomized, Placebo-Controlled, Crossover Trials. (PubMed, CNS Drugs) - "Our results suggest that previous long-term dopaminergic treatment, even before clinical augmentation is reached, induces pathophysiological changes in RLS that impair future responses to both dopaminergic and non-dopaminergic therapies. Our findings confirm previous results with gabapentin enacarbil and suggest that these changes develop well before clinical augmentation appears. Pathophysiological implications for the understanding of dopaminergic augmentation are discussed. Our results support the American Academy of Sleep Medicine (AASM) recommendation against using dopamine agonists as the initial choice for RLS treatment."

Journal • Retrospective data • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Identifying responders to gabapentin for the treatment of alcohol use disorder: an exploratory machine learning approach. (PubMed, Alcohol Alcohol) - "Baseline drinking levels and anxiety levels may be associated with the protracted withdrawal syndrome, previously implicated in the clinical response to gabapentin. However, these analyses underscore motivation for change and self-efficacy as predictors of clinical response to GE-XR, suggesting these established constructs should receive further attention in gabapentin research and clinical practice. Multiple studies using different machine learning methods are valuable as these novel analytic tools are applied to medication development for AUD."

Clinical • Journal • Addiction (Opioid and Alcohol) • Mood Disorders • Psychiatry

Treatment of Restless Legs Syndrome Improves Agitation and Sleep in Persons With Dementia: A Randomized Trial. (PubMed, J Am Med Dir Assoc) - "Our findings suggest a novel approach for nighttime agitation in persons with dementia: assessing for RLS and initiating interventions. Larger and longer trials are needed."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Leveraging the Genetics of Psychiatric Disorders to Prioritize Potential Drug Targets and Compounds. (PubMed, medRxiv) - "We also observed genetic support for other commonly used psychotropics (e.g., clozapine, risperidone, duloxetine, lithium, and valproic acid). Opportunities for drug repurposing were revealed such as cholinergic drugs for ADHD, estrogens for depression, and gabapentin enacarbil for schizophrenia...Here we present a series of complimentary and comprehensive analyses that highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders. Our findings present novel opportunities for refining psychiatric treatment."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Bipolar Disorder • CNS Disorders • Depression • Mental Retardation • Mood Disorders • Psychiatry • Schizophrenia • CYP2D6

Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. (PubMed, J Clin Sleep Med) - "The following recommendations are intended as a guide for clinicians in choosing a specific treatment for RLS and PLMD in adults and children. Each recommendation statement is assigned a strength ("Strong" or "Conditional"). A "Strong" recommendation (i.e., "We recommend…") is one that clinicians should follow under most circumstances. The recommendations listed below are ranked in the order of strength of recommendations and grouped by class of treatments within each PICO question. Some recommendations include remarks that provide additional context to guide clinicians with implementation of this recommendation."

Clinical guideline • Journal • Chronic Kidney Disease • Movement Disorders • Nephrology • Obstructive Sleep Apnea • Pediatrics • Renal Disease • Respiratory Diseases • Restless Legs Syndrome • Sleep Disorder

Unraveling Shared Diagnostic Biomarkers of Fibromyalgia in Ankylosing Spondylitis: Evidence from Comprehensive Bioinformatic Analysis and Experimental Validation. (PubMed, J Inflamm Res) - "Gabapentin enacarbil was recognized as a potential therapeutic drug for AS-FM patients...Meanwhile, these results were confirmed in clinical samples. CETN3 and CACNA1E may become potential diagnostic biomarkers and therapeutic targets for patients with AS complicated by FM."

Biomarker • Journal • Ankylosing Spondylitis • CNS Disorders • Fatigue • Fibromyalgia • Immunology • Inflammatory Arthritis • Musculoskeletal Pain • Pain • Rheumatology • Seronegative Spondyloarthropathies • Sleep Disorder • CACNA1E • CACNG3

RLS TREATMENT REDUCES NIGHTTIME AGITATION AND INCREASES SLEEP DURATION IN OLDER ADULTS WITH ALZHEIMER'S DISEASE (SLEEP 2024) - "Support (if any): R01AG051588 UL1TR003015 Arbor - Horizant and placebo... Our results clearly show that RLS is an unrecog nized cause for nighttime agitation in older adults with dementia and that treatment of RLS with GEn, compared to placebo, sig nificantly reduced nighttime agitation and improved sleep"

Clinical • Alzheimer's Disease • CNS Disorders • Dementia • Restless Legs Syndrome • Sleep Disorder

Reductions in World Health Organization risk drinking level are associated with improvements in sleep problems among individuals with alcohol use disorder. (PubMed, Alcohol Alcohol) - "Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Sleep Disorder

Reductions in World Health Organization Risk Drinking Level Are Associated With Reductions in Alcohol Use Disorder Diagnosis and Criteria: Evidence From an Alcohol Pharmacotherapy Trial. (PubMed, J Addict Med) - "World Health Organization risk drinking level reductions correlate with Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria, providing further evidence for their use as endpoints in alcohol intervention trials, which has potential implications for broadening the base of AUD treatment."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Mental Retardation • Psychiatry

A COMPREHENSIVE UPDATE on the ADMET CONSIDERATIONS for α2δ CALCIUM CHANNEL LIGAND MEDICATIONS for TREATING RESTLESS LEGS SYNDROME. (PubMed, Expert Opin Drug Metab Toxicol) - "However, we highlight the linear kinetic of gabapentin enacarbil and pregabalin, differently from gabapentin. The use of α2δ ligands is associated to poor risk of augmentation. We still need new long-term safe and effective treatments, which could be developed along with our knowledge of RLS/WED pathophysiology."

Journal • Review • CNS Disorders • Insomnia • Mood Disorders • Movement Disorders • Musculoskeletal Pain • Pain • Psychiatry • Restless Legs Syndrome • Sleep Disorder

Evaluation of Abuse Potential of HORIZANT Taken Alone and With Oxycodone in Healthy, Nondependent Recreational Opioid Users (clinicaltrials.gov) - P4 | N=110 | Completed | Sponsor: Azurity Pharmaceuticals

Combination therapy • New P4 trial • Addiction (Opioid and Alcohol)

An Abuse Potential Study of Orally Administered HORIZANT in Healthy, Non-dependent, Recreational Drug Users (clinicaltrials.gov) - P4 | N=86 | Completed | Sponsor: Azurity Pharmaceuticals

New P4 trial

Restless Legs Syndrome and Other Common Sleep-Related Movement Disorders. (PubMed, Continuum (Minneap Minn)) - "α2δ Ligands, such as gabapentin enacarbil, can be used for the initial treatment of restless legs syndrome (RLS) or in those who cannot tolerate, or have developed augmentation to, dopamine agonists...Dopaminergic medications can be very effective but often lead to augmentation, which limits their long-term use. Other sleep-related movement disorders to be aware of are sleep-related rhythmic movement disorder, nocturnal muscle cramps, sleep-related propriospinal myoclonus, sleep bruxism, and benign myoclonus of infancy."

Journal • Cardiovascular • Dental Disorders • Hematological Disorders • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Therapeutic Strategies for Postherpetic Neuralgia: Mechanisms, Treatments, and Perspectives. (PubMed, Curr Pain Headache Rep) - "In terms of treatment, guidelines recommend patients use tricyclic antidepressants (TCAs), gabapentin, pregabalin, and 5% lidocaine patches as the first-line medications, and gabapentin is investigated most, especially the gabapentin enacarbil (GEn). Combinational therapies may be used when a single therapy cannot achieve the desired effect. Therapies such as OMT and EA have also been proposed to palliate pain in some cases, and future directions of treatment may be investigated in Chinese medicine and acupuncture."

Journal • Review • Anesthesia • Neuralgia • Pain

Gabapentin as a Pre-emptive Analgesic in Oral and Maxillofacial Surgical Procedures (clinicaltrials.gov) - P4 | N=0 | Withdrawn | Sponsor: Massachusetts General Hospital | N=30 ➔ 0 | Unknown status ➔ Withdrawn

Enrollment change • Trial withdrawal • Pain

Network-Based Data Analysis Reveals Ion Channel-Related Gene Features in COVID-19: A Bioinformatic Approach. (PubMed, Biochem Genet) - "Drug-target enrichment analysis showed that the relevant drugs targeting the hub genes CACNA2D1, CACNA1A, CACNA1E, KCNA2 and KCNA5 were gabapentin, gabapentin enacarbil, pregabalin, guanidine hydrochloride and 4-aminopyridine. The results of this study provide a valuable basis for exploring the mechanisms of ion channel genes in COVID-19 and clues for developing therapeutic strategies for COVID-19."

Journal • Ataxia • CNS Disorders • Developmental Disorders • Infectious Disease • Mental Retardation • Movement Disorders • Nicotine Addiction • Novel Coronavirus Disease • Psychiatry • Respiratory Diseases • CACNA1A • FOXC1 • GATA2 • MIR129 • MIR129-2 • MIR146A • MIR27A • MIR335 • MIRLET7B • TRPC1

Gabapentin Implicated in Overdose Deaths (RheumNow) - "Recent FDA and MMWR warnings suggest that gabapentin was present and implicated in almost 10% of US overdose deaths between 2019 and 2020. This CDC report also stated that gabapentin was the cause of the death in half of these cases. Despite its FDA approval for the management of seizures and pain from herpes zoster, off-label use of gabapentin in pain and neuropathy resulted in a doubling of gabapentin prescriptions from 13 to 27 per 1000 insurance claims between 2009 and 2016. In 2019 gabapentin was teh 7th most prescribed drug in the USA."

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